Use of 2-deoxy-D-glucose & PI3K/Akt pathway inhibitors in head & neck cancer ther

2-脱氧-D-葡萄糖的用途

基本信息

批准号：
7661982
负责人：
Andrean Llewela Burnett
金额：
$ 10.91万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7661982
关键词：
Antioxidants Biochemical Cancer Biology Cell Cycle Progression Cells Cetuximab Combined Modality Therapy Defect Deoxyglucose Dose Drug Metabolic Detoxication Electrons Energy Metabolism Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Exhibits Family Glucose Glucosephosphate Dehydrogenase Glycolysis Glycolysis Inhibition Goals Head Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Hydrogen Peroxide In Vitro Ionizing radiation Laboratories Lead Malignant Neoplasms Measures Mediating Metabolic Metabolism Mitochondria NADP Natural regeneration Normal Cell Oxidative Stress Oxygen Pathway interactions Pentose Phosphate Cycle Pathway Pentoses Perifosine Peroxidases Peroxides Phosphotransferases Play Positron-Emission Tomography Pre-Clinical Model Predisposition Production Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Pyruvate Pyruvates Radio Reactive Oxygen Species Receptor Signaling Relative (related person)Research Resistance Respiration Role Signal Pathway Solid Neoplasm Source Superoxides Testing Therapeutic Agents Therapeutic Intervention Work angiogenesis base cancer cell cancer therapy cell growth cell transformation chemotherapeutic agent combined cancer modality therapy cytotoxicity deprivation design glucose metabolism glucose uptake glutathione peroxidase in vivo inhibitor/antagonist killings mitochondrial dysfunction neoplastic cell overexpression receptor therapy design thioredoxin peroxidase tumor wortmannin

项目摘要

DESCRIPTION (provided by applicant): Activation of the PI3K/Akt pathway is observed frequently in human head and neck cancer (HNSCC) and its activation has been found to induce a dose-dependent stimulation of glycolysis in cancer cells, which correlates with a more aggressive malignancy in vivo. Increased glucose metabolism in cancer cells (compared to normal cells) is believed to function as a compensatory mechanism protecting from intracellular hydroperoxides formed as byproducts of altered mitochondrial respiration via the formation of pyruvate and NADPH. Furthermore, increased glucose metabolism (measured by FDG-PET) has been associated with increased sensitivity to glucose deprivation using the glycolytic inhibitor 2-deoxy-D-glucose (2DG). The current proposal tests the hypotheses: Inhibition of Akt/EGFR signaling will significantly enhance 2DG-induced radio-/chemo-sensitization via metabolic oxidative stress in human head and neck cancer cells in vitro and in vivo. A corollary hypothesis that will also be tested is that the extent to which human head and neck cancer cells in vivo take up FDG as determined by PET imaging will predict sensitivity to combined modality cancer therapies based on inhibition of Akt/EGFR signaling combined with 2DG. Aims 1 and 2 will determine if 2DG-induced radio-sensitization can be enhanced by inhibitors of the PI3K/Akt pathway [i.e., LY294002, perifosine, wortmannin] and/or chemotherapeutic agents believed to inhibit the activation of EGFR [i.e., erlotinib and cetuximab] in human head and neck cancer cells via metabolic oxidative stress in vitro and in vivo. Aim 3 will determine if the extent of 2DG+Akt/EGFR inhibitor-induced radio-sensitization and oxidative stress can be predicted by glucose uptake as determined by FDG-PET. The long term goal of this work is to provide a biochemical rationale for the use of glycolytic inhibitors, using 2DG, PI3K/Akt pathway inhibitors and/or EGFR inhibitors, to develop combined modality therapies to treat HNSCC based on tumor specific sensitivity to glucose deprivation and metabolic oxidative stress.

描述（由申请人提供）：在人类头颈癌 (HNSCC) 中经常观察到 PI3K/Akt 通路的激活，并且已发现其激活可诱导癌细胞中糖酵解的剂量依赖性刺激，这与更多的相关性相关。体内侵袭性恶性肿瘤。癌细胞中葡萄糖代谢的增加（与正常细胞相比）被认为是一种补偿机制，可防止细胞内氢过氧化物的产生，氢过氧化物是线粒体呼吸改变通过丙酮酸和 NADPH 的形成而形成的副产物。此外，葡萄糖代谢的增加（通过 FDG-PET 测量）与使用糖酵解抑制剂 2-脱氧-D-葡萄糖 (2DG) 时对葡萄糖剥夺的敏感性增加相关。目前的提案测试了以下假设：抑制 Akt/EGFR 信号传导将在体外和体内人头颈癌细胞中通过代谢氧化应激显着增强 2DG 诱导的放射/化学敏感性。还将测试的一个推论假设是，通过 PET 成像确定的人头颈癌细胞体内摄取 FDG 的程度将预测基于 Akt/EGFR 信号传导抑制与 2DG 结合的联合癌症疗法的敏感性。目标 1 和 2 将确定 2DG 诱导的放射增敏是否可以通过 PI3K/Akt 通路抑制剂 [即 LY294002、哌立福辛、渥曼青霉素] 和/或据信抑制 EGFR 激活的化疗药物 [即厄洛替尼和西妥昔单抗]在体外和体内通过代谢氧化应激作用于人头颈癌细胞。目标 3 将确定是否可以通过 FDG-PET 测定的葡萄糖摄取来预测 2DG+Akt/EGFR 抑制剂诱导的放射增敏和氧化应激的程度。这项工作的长期目标是为使用糖酵解抑制剂提供生化原理，使用 2DG、PI3K/Akt 通路抑制剂和/或 EGFR 抑制剂，根据肿瘤对葡萄糖剥夺的特异性敏感性开发治疗 HNSCC 的联合疗法和代谢氧化应激。